Method for reducing plasma lipid levels

ABSTRACT

PLASMA LIPID LEVELS ARE REDUCED BY INTERNALLY ADMINISTERING A PHENOL HAVING A NITROGEN-CONTAINING GROUP BONDED TO THE PHENOLIC NUCLEUS. A TYPICAL NITROGEN-CONTAINING GROUP IS   -CH2-N(-R)-R&#39;&#39;   EXEMPLARY PHENOLS ARE 2,6-DI-TERT-BUTYL-A:DIMETHYLAMINO-P-CRESOL, A,A&#39;&#39;-(METHYLIMINO)BIS(2,6-DI-TERT-BUTYL-P-CRESOL) AND A2,A4,A6-TRIS(DIMETHYLAMINO)MESITOL. TRINUCLER PHENOLS ARE ALSO DISCLOSED AS ARE SALTS SUCH AS HYDROCHLORIDES.

United States Patent M 3,809,761 METHOD FOR REDUCING PLASMA LIPID LEVELS Sidney I. Lerner, Cincinnati, Ohio, assignor to Ethyl Corporation, Richmond, Va.

No Drawing. Continuation-impart of application Ser. No. 19,080, Mar. 12, 1970, now Patent No. 3,714,365, which is a continuation-in-part of abandoned application Ser. No. 357,777, Apr. 6, 1964. This application Nov. 10, 1972, Ser. No. 305,455

Int. Cl. A61k 27/00 US. Cl. 424-330 1 Claim ABSTRACT OF THE DISCLOSURE llasma lipid levels are reduced by internally administering a phenol having a nitrogen-containing group bonded to the phenolic nucleus. A typical nitrogen-containing group is /R -CH,N

Exemplary phenols are 2,6-di-tert-butyl-a-dimethylaminop-cresol, a,a'- (methylitnino) bis(2,6-di-tert-buty1-p-cresol) and a ,u ,a -tris(dimethylamino)mesitol. Trinuclear phenols are also disclosed as are salts such as hydrochlorides.

CROSS-REFERENCE TO RELATED APPLICATIONS This is a continuation-in-part of application Ser. No. 19,080, filed Mar. 12, 1970, now US. Pat. No. 3,714,365, which in turn is a continuation-in-part of application Ser. No. 357,777, filed Apr. 6, 1964, now abandoned.

BACKGROUND AND DESCRIPTION OF THE INVENTION In the above-mentioned parent applications, I disclosed that phenols of a class therein exemplified and defined, will reduce mammalian plasma lipid levels upon internal administration to a mammal to be so treated. This application pertains to that subject matter and to preferred embodiments thereof. One preferred embodiment comprises use of u ,a ,a -tris(dimethylamino)mesitol mentioned on page 6, lines 26-27 of application Ser. No. 357,777 and page 8, lines 26-27 and column 11, lines 20-60 of US. 3,714,365. Moreover, this invention pertains to use of acid salts of the aminophenols of the parent. Such salts are readily made by reacting the corresponding phenol with acid. For example, 2,6-di-tert-butyl-a-dimethylamino-pcresol yields the corresponding hydrochloride salt upon dissolving 100 grams of the phenol in 1 liter of hexane and 150 ml. of tetrahydrofuran and bubbling HCl gas into the mixture until no more is absorbed or until precipitation is complete. As appreciated by a skilled practitioner, analogous techniques are applicable to the aminophenols herein and likewise, other acids can be employed. Preferred acids are those commonly employed in therapeutic salts as hydrochloric, hydrobromic, sulfate, phosphate, acetate, tartrate, citrate, and the like. In those instances where such inorganic acids, lower fatty acids, and lower dibasic and tribasic acids alter the solubility characteristics of the aminophenol, this can be taken advantage of in formation of various dosage unit forms of this invention. The organic acids applicable herein and exemplified above preferably have from two to six carbon atoms. In general, the dosage of the salts is about that calculated by multiplying the correct molar or weight ratio of salt to amine parent by the dosage of the parent compound. Of course, where the salt has some difference in solubility,

adsorption or rate of metabolism, excretion, or similar characteristic this dosage can be commensurately altered. Of the salts the hydrochlorides are preferred for their low cost. A highly preferred salt is the hydrochloride prepared in the above exemplary preparation.

' This invention relates to a method and composition for reducing plasma lipid levels and particularly cholesterol, triglyceride and phospholipid levels.

Prior to this invention there has been a great need for an effective antihyperlipemic agent which is low in toxicity and is relatively free of undesirable side effects. For example, it is believed that coronary artery disease and atherosclerosis in man are associated with an abnormally high concentration of cholesterol and other lipids in the blood stream. Of particular significance is the concentration of the ,B-lipoprotein fraction in the blood. The reduction of the amount of these lipids, including not only free and esterified cholesterol, but also phospholipids and triglycerides, is of major importance in the prevention and treatment of coronary artery disease, atherosclerosis, other vascular and heart ailments and disorders of lipid metabolism.

It is therefore an object of this invention to provide a method for reducing plasma lipid levels, particularly cholesterol triglyceride and phospholipid levels. Another object is to provide a pharmaceutical composition capable of lowering plasma lipid levels when internally administered. Still another object is to provide such reductions without untoward side efiects. A further object is to provide pharmaceutical compositions suitable for oral administration. A still further object is to provide such compositions which effectively lower the ,B-lipoprotein fraction of serum lipids.

According to one embodiment of this invention, the above and other objects are accomplished by providing a method of lowering plasma lipid levels which comprises internally administering a compound of this invention in an amount sufiicient to lower the plasma lipid level. The compounds of this invention are as follows:

wherein: R is selected from the group consisting of alkyl, cycloalkyl, aryl and aralkyl; R and R when taken collectively with the connector carbon atom C, are

and when taken separately, are each independently selected from hydrogen and R; R and R when taken collectively with the nitrogen atom N, are from the group consisting of pyridene, piperazine, piperidine and morpholine, and when taken separately, are each independently selected from hydrogen and R; a is from 0-4; and b and e are eachindependently selected from 0 and 1.

In the above hydroxybenzylamines, it is preferred that alkyl have from 1-20 carbon atoms, cycloalkyl have from 612 carbon atoms, aryl have from 612 carbon atoms and aralkyl have from 7l2 carbon atoms. The alkyl substituents may be unsaturated, for example, olefinic, but it is preferred that they be saturated, or paraffinic. Examples of such compounds include:

(cyclohexyl) (n-octyl) -amino] -u -cyclohexyl-2,4-

xylenol;

3,S-diethyl-Z-hydroxy-N-(3'-eicosyl)-N-p-methylphenylthiobenzamide;

a,a'-[ (a-methylbenzyl) imino] bis(3-cyclohexyl-2,5-di-nheptyl-6-isopropy1-p-cresol) 3 -tert-amyl-2-sec-butyl-4-n-hexyl-a-p -ethylbenzyl-u- (ethyl) -o-n-propylb enzyl -amino] -m-cresol;

' iSObUtYl-a- ('-hcxadecyl) -4- (2'-octy1)-o-cresol] ee-arnino-p-cresoi;

a-n-dodecyl-Z-ethyl-S-m-ethylbenzyl-a-phenyl-a-(nde cylamino) -p-cresol a',e",u"-nitrilotris [3 ,5 -di-tcrt-amyla- (p-tert-amylbenzyl) -o-cresol] 2-o-ethy1phenyl-3 -methyl-5-phenyl-6- (di-o-isopropylphenyl) -e-pyridino-p-cresol;

wn-propyl-m- (p-sec-butylcyclohexyl) m-phenylphenyl) amino] -o-cresol;

a',m",a"'-nitrilotris[ 3- a-methylbenzyl -6-pethylcyclohexy1-2-(2-tetradecyl) -a-thiO-P-CI'6SOI] ao-p-dimethylcyclohexyl) -a- 3-eicosyl) -5-ethyl-4-p-namylphenyl-3-phenyl-a-hexadecyl-amino-o-cresol;

e-isopropy1-u-{ (p-isopropylphenyl (m-ethylcyclohexyl) amino] -m-cresol;

a,e'-n-butyliminobis 2,5 -di-p-methylphenyl-4-thiocarbonylphenol) 2-11-dodecyl-S-o-isopropylbenzyl-3-o-phenylcyclohexy1-a- (a,a-diethylb enzyl) -pcresol;

6 (3 '-eicosyl) -4-pheny1-2- [piperazino (thiocarbonyl) phenol;

e ,a (methylimino) bis[ 6- (di-o-ethylcyclohexyl) -2,4-

xylenol] 3-tert-butyl-6- (4-heptodecyl) -a-phenylcyclohexyl-arphenylphenyl-a- (tcrt-amyl) (o-n-butylphenylpamino] -o-cresol;

a-tert-amyl-Z- a, a-diethyl-benzyl )-u-n-heptyl- S-m-isoa-tert-amyl-2-( u,a-diethylbenzyl -u-n-heptyl-5-rn-isohexyl) (p-n-hexylcyclohexyl -amino] -o-cresol;

a,e'-(n-heptylimino bis 3- (4'-nonadecyl) -6-(3-octadecyl) -5-n-propyl-pcresol] 6 -tert-butyl-u -dimethylamino-2,4-xylenol;

a-dimethylamino-o-cresol;

a-dimethylamino-p-cresol;

2,6-di-tert-butyl-4-( l-dimethylamino-Z-methyl-n-propyl) phenol;

a-dimethylamino-4,6-bis( l-methyl-n-heptyl -o-cre sol and 4( l ,1,3,3-tetramethyI-n-butyl)-a -dirnethylarnino-2,6-

xylenol In another embodiment of this invention 1 provide a composition having anticholesterolemic and antilipemic activity comprising a suitable pharmaceutical carrier and a pharmaceutically effective amount of a hydroxybenzylamine as described above.

While the compounds described above by Formula I are all generally useful in this invention, certain structures are preferred. Preferred compounds comprise those compounds of Formula I in which the hydroxyl group is in the para position; R and R are when taken together with the connector atom C, and when taken separately are hydrogen; a. is 2 and each R is positioned ortho to the hydroxyl group. Such compounds are generally easier and more economically prepared and are more effective than the other compounds. These diorthosubstituted p-hydroxybenzylamines have the formula:

wherein R and R when taken collectively with the connecting carbon atom C are 4 and when taken separately, are hydrogen. Examples of such compounds include:

2,6-dimethyl-a- (p-n-propylcyclohexyl) (n-tridecyl) amino] -p-creso1;

3-sec-amy1-4-hydroxy-5 -phenyl-N,N-di- (a-ethyl-nt-npropylbenzyl) thiobenzamide;

2-p-ethylcyclohexy1-6-sec-butyl a-[ (3 '-tetradecyl) amino] -p-cresol;

Z-cyclohexyl-fi- (a,,3-diethyl-p-methylbenzyl) -u morpholino-p-cresol;

Z-p-methyleyclohexyl- 6- 3 '-nonyl) *u- (n-hexyl) (ocyclohexyl) -amino-p-creso1;

3- (2'-hepty1) -4-hydroxy-S-pphenylphenyl-N- (ct-methylbenzyl) -N- 4'-heptadecyl) thiobenzamide;

2,6-di-tert-butyl-a- (methyl) (phenyl) -amino] -pcresol;

u,oc'-[ (dimethylbenzyl) imino] bis [2-benzyl-6- (4- eicosyl) -p-cresol;

3 (2-dodecyl) -4-hydroxy-5-m-methylphenyl-N-o-ethylphenyl-N-n-octadecyl thiobenzamide;

Z-n-hexadecyl-6-methyl-a-piperidino-pcresol;

2- (a-methylbenzyl) -6-o-phenylcyclohexy1-a- (P-namylphenyl) (3 -nonyl) -amino] -p-cresol;

a-d imethylamino-2,6-bis (a-methylbenzyl) -p-cresol;

ct,a'- (methylimino) bis [2.6-bis [a-methylbenzyl) -pcresol];

aged-2,6-diethylphenylimino) bis (2,6-di-tert-butyl-pcresol) a-dimethylamino-2,6-bis( a,u-dimethylbenzyl) -p-cresol- 6- (u-methylbenzyl -u -dimethyl am inc-2,4-xylenol;

6-tert-butyl-a -dimethylamino-2,4xylenol;

2,6-dicyclohexyl-u-dimethylamino-p-cresol;

2,-6-di-tert-butyl-u- (N-methylanilino) -pcresol; and

2,6-di-tert-butyl-wdicyclohexylamino-p-cresol.

The most preferred group of compounds are those of Formula II in which one R is an alkyl group of from 1-12 carbon atoms, the other R is an alpha-branched alkyl group of from 3-12 carbon atoms and R and R are, collectively with the nitrogen atom, the morpholine group, and separately are selected from hydrogen and alkyl of from 18 carbon atoms. These compounds are generally the most efliectixg and most economically prepared. Examples of such compounds include:

3,5-di- (2'-hexyl) -4-hydroxy-N-n-hexyl-N-isobutyl thiobenzamide;

ct,on' (methylimino bis [2- (3-nonyl) -6-n-propyl-pcresol];

3-(4'-tlodecyl)-S-ethyl-Lhydroxy-N-n-amyl-N-(2'- hexyl) thiobenzamide;

2-isopropyl-6-n-octyl-e-(tert-amyl)-(n-hexyl)-amino-pcresol;

e,m'- (ethylimino)bis[2-sec-butyl-6-(3-undecyl)-pcresol];

3-(2'-heptyl)-4-hydroxy-5-methyl-N,N-di-n-propylthiobenzamide;

2-n-amyl-6-(4'-dodecyl)-a-morpholino-p-cresol;

u,a',a"-nitrilotris (2-ethyl-fi-isopropyl-p-cresol) a-dimethylamino-Z,6-diisopropyl-p-cresol;

a,ot'- (methylimino) bis (2,fi-di-tert-butyl-p-cresol) 2,6-di-tert-butyl-a-morpholino-p-cresol;

6-tert butyl-a -dimethylamino-2,4-xylenol;

,u,ot"-nitrilotris (2,6-di-tert-butyl-p-cresol) 3,S-di-tert-butyl-4-hydroxy-N,N-dimethyl-thio-benzamide;

2,6-di-tert-butyl-u-di-n-butylamino-p-cresol;

5-tert-butyl-4-hydroxy-N,N-dimethy1thio-m-toluamide;

2,6-di-tert-butyl-a-tert-butylamino-p-cresol;

6-( l, 1,3 ,3-tetramethyl-n-butyl) -a -dimethylamino-2,4-

xylenol and a-bis(2-ethyl-n-hexyl) amino-2,6-di-tert-hutyl-p-cresol.

The most preferred compound, and generally the most effective, is 2,6-di-tert-butyl-e-dimethylamino-p-cresol.

The compounds of this invention can be prepared by methods well known to the art. In general an appropriate phenol is reacted with an appropriate aldehyde (where at least one alpha substituent on the benzyl group is hydrogen), or an appropriate ketone, and a primary or secondary amine in which the hydrocarbon or heterocyclic portion thereof is in conformity with the groups designated hereinabove as R and R In such processes a monohydric alcohol of from 1 to 6 carbon atoms can conveniently be used. Details of such processes can be found in the art, for example, in US. Pat. 3,043,774.

Where R and R and R and R with the connector carbon atom C, are collectively such compounds can be prepared by reacting the corresponding hydroxybenzyl amine with sulfur. Another method is to react the corresponding hydroxybenzaldehyde with sulfur and an appropriate amine. The hydroxybenzaldehydes used in this latter process can be obtained by bromination of the corresponding cresol in the presence of alcohol with subsequent hydrolysis of the brominated cresol.

Also included as anticholesterolemic and antilipemic agents within the scope of this invention are hydroxybenzylamines of Formula I which are substituted with one or more of the following groups: N; NO 7)2;

ll ll -CR GOR and halogen, such as Cl and Br; where R-; is selected from the group consisting of hydrogen and R, R being as defined above following Formula I. These substituents may be in one or more positions on the ring or one or more may be on one or more of the hydrocarbon or heterocyclic substituents described above. When R and R or R and R collectively with the connector carbon atom C, are the piperazine group, the outermost nitrogen atom may be substituted with Examples of such compounds include:

a ,ot ,a -tris (dimethylamino) mesitol;

2,2- 3,5-di-tert-butyl-4-hydroxybenzylimino diethanol;

a,a-( 1,4-piperazinediyl)bis(2,6-di-tert-butyl-p-cresol;

,a'- 1,4-piperazinediyl) bis 3,5-di-tert-butyl-4-hydroxythiobenzaldehyde) and 2,6-di-tert-butyl-4- (2-methyl-2-nitro-n-propyl) phenol.

The compounds of this invention effectively reduce circulating serum lipid levels using very low dosage regimens. This allows use in pharmaceutical forms which are both convenient for administration and pleasant for consumption by the patient.

To demonstrate the outstanding effectiveness of the compounds of this invention, and by way of example, tests are performed on dogs (Beagles) which are separated into four groups. The control group is maintained on a diet of Allied Mills-Tail Wagger Dog Food-Krums to which is added 5.0 weight percent of a corn oil. The Experimental Groups I, II and III are maintained on the same diet as the Control Group except that a compound of this invention is added to the extent of 0.3, 1.0 and 3.0 weight percent, based on the weight of the dog food, respectively. The compound is added by dissolving it in the corn oil up to the limit of solubility and thereafter thoroughly mixing any additional amount of compound with the dog food. After 30 days, samples of plasma and serum are taken and the serum analyzed for total lipid, total cholesterol, free cholesterol and cholesterolester values. The serum from the dogs in the Experimental Groups are found to contain significantly less total lipid, total cholesterol, free cholesterol and ester cholesterol than the serum from the dogs in the control group.

After days of being maintained on the above diets, dogs in the control group and experimental groups are sacrificed and their plasma and serum are analyzed for cholesterol, phospholipid and triglyceride values. The serum from the dogs in the experimental groups are found to contain significantly less cholesterol phospholipid and triglyceride than the serum from the control group.

The amount of aand fl-lipoprotein in the serum for each group is then determined by ultracentrifugation. Serum from the dogs in the experimental groups are found to contain significantly less a-lipoprotein and ,8- lipoprotein than serum from the control group.

The compounds of this invention give outstanding reductions in lipid and lipoprotein values, particularly in the fl-lipoprotein values. High ,B-lipoprotein values are generally associated with atherosclerosis in man.

Eflicacious results are also obtained using compounds of this invention with other mammals such as cattle, sheep, rabbits, and others, and this invention is particularly desirable for treating humans.

In contrast to antilipemic agents heretofore available, the compounds of this invention possess distinct advantages with respect to safety for human treatment and with respect to untoward side effects.

The compounds are administered internally and may be parenterally or orally administered, the latter being pref erable. For oral administration, pharmaceutical preparations of this invention may be made by following the conventional techniques of the pharmaceutical chemist. These techniques involve granulating and compressing when necessary or variously mixing and dissolving or suspending the ingredients as appropriate to the desired end product. Numerous pharmaceutical forms to carry the compounds can be used. For example, the pure compound can be used or it can be mixed with a solid carrier. Generally, inorganic pharmaceutical carriers are preferable and particularly solid inorganic carriers. One

reason for this is the large number of inorganic materials which are known to be pharmaceutically safe and acceptable, as well as very convenient in preparing formulations. The compositions may take the form of tablets, linguets, powders, capsules, slurries, troches or lozenges and such compositions may be prepared by standard pharmaceutical techniques. Tablet compositions may be coated or uncoated and they may be effervescent or non-effervescent. Conventional excipients for tablet formations may be used. For example, inert diluents, such as magnesium carbonate or lactose, distintegrating agents such as maize starch or alginic acid, and lubricating agents such as magnesium stearate may be used. A preferable tablet composition is one which comprises from about 10 to about 500 milligrams of a compound of this invention.

If a liquid carrier is used, the preparation may be in the form of a soft gelatin capsule, a syrup, a liquid solution or suspension.

The hydrocarbon solubility of most of the compounds of this invention is high enough to allow the use of pharmaceutically-acceptable oils as carriers. For example vegetable or animal oils such as sunflower oil, safiiower oil, maize oil or codliver oil can be used. Glycerine can also be used. With this latter solvent, from 25 to 30 percent water may be added. When water alone is the carrier, or when the solubility of the compound in the oil is low, the preparations can be administered in the form of a slurry.

Emulsion compositions may be formulated using emulsifying agents such as sorbitan trioleate, polyoxyethylene sorbitan monooleate, lecithin, gum acacia or gum tragacanth. Aqueous based suspensions may be prepared with the aid of wetting agents such as polyethylene oxide condensation products of alkylphenols, fatty alcohols or fatty acids and with suspending agents, for example a hydrophilic colloid such as polyvinylpyrrolidone. The emulsions and suspensions may contain conventional excipients such as sweeting agents, flowing agents, coloring materials and preservatives.

The compounds of this invention may be administered in the form of a nutritive preparation in which the active ingredient is mixed with proteins, such as casein, and carbohydrates. In adidtion to the active ingredient, dietary supplements such as vitamins, salts of glycerophosphoric acid, choline, inositol and amino acids such as methionine may be added.

The percentage of the compound to be used in the pharmaceutical carrier may be varied. It is necessary that the compound constitute a proportion such that a suitable dosage will be obtained and it is preferred to use pharmaceutical compositions containing at least 10 weight percent of the compound. Activity increases with concentration of the agent in the carrier, but those compositions containing a significant amount of carrier, e.g. at least 1 percent and preferably at least 5 percent, are preferred as they allow for the easier administration of the compound.

For parenteral use, the compounds of this invention can be formulated with sterile ingredients, compounded and packaged asceptically. They may be administered intravenously or intramuscularly. Useful solvents for formulation in such use are the polyhydric aliphatic alcohols and mixtures thereof. Especially satisfactory are the pharmaceutically acceptable glycols, such as propylene glycol, and mixtures thereof. Glycerine is another example of a polyol which is particularly useful. Up to 25-30 percent by volume of water may be incorporated in the vehicle if desired. An 80 percent aqueous propylene glycol solution is a particularly convenient solvent system. A pH range, about 7.4, and isotonicity compatible with body isotonicity, is desirable. Basicity may be controlled by addition of a base as required, and a particularly convenient base is monoethanolamine. It may often be desirable to incorporate a local anaesthetic and such are well known to those skilled in the art. For example, lidocaine (fl-di-ethylamine-Z,-acetoxylidide, available from the Astra Chemical Co.), may be employed at a level of up to about 20 mg./cc., or even more.

It is not intended that the dosage regimens of the compounds be limited to any particular range. The dosage range desired in this invention is that range necessary to accomplish the desired end of lowering serum lipid levels. The amount of lipid level reduction desired will not be the same for all patients, but depends on such factors as initial lipid level, predominance of one form of lipid over another, etc. The dosage, whether oral or parenteral must, therefore, or necessity be individually determined by the physician or veterinarian. Likewise the concentration range of the compounds in the various formulations of this invention is not limited. The concentration should be high enough to avoid an excessive number of administrations per day, but low enough to allow flexibility in administration.

Administration of the compounds of this invention by the oral route is preferred. Preferred daily dosages can be as low as mg. for a human. Higher dosages can be given. Generally, one uses as small a dose as will afford the desired response. This reduces chance of appearance of undesirable side effects. A convenient upper limit is about 60 grams per person per day. A preferred range of daily dosage is about 0.5 to 7.5 grams. In terms of body weight preferred dosages are from 0.8 to 1000 mg. per kg. of body weight per day with a preferred range of about 5 to 125 mg. per kg. of body weight per 'iday. The daily dosage is preferably administered from one to four or five times daily in amounts of from about 10 mg. to about 2000 mg., and these amounts may be administered in dosage units containing at least 0.5 mg. of

the compound. For example, when administrating the compound in tablet form several tablets containing from, say 0.5 to 25 mg. of active compound can be administered, up to 4 or more times daily. Alternatively, larger dosage units containing more of the compound, say 25 to 500 mg, can be administered at less frequent intervals.

For parenteral applications daily dosages of from about one-half to about one-tenth of the oral dosages are preferred. Thus daily dosages can be as low as 1.0 mg. for a human or about 0.02 mg. per kg. for body weight. The

maximum dosage is determined only by physical limita-' tions. A convenient upper limit is about 6 grams. From about 0.5 to about 1000 mg. per injection (dosage unit) in concentrations of about 0.5 to 200 mg/c.c., with from 1 to 3 injections of from 1 c.c. to 10 c.c. daily will give the required amount. Preferred formulations will contain from 5 to about 150 mg./c.c. to be given in one injection of from 1 c.c. to 5 c.c.

Larger or smaller doses can be used and, in some cases, might be preferred in individual cases. Likewise administration need not be on a daily basis, although this is preferred, but may be, for example, on alternate days or even weekly and the like. With either oral or parenteral use, a daily regimen is preferred. However, even a single administration has some effect.

Typical formulations of this invention are described in the following examples in which all parts are by weight. The compounds in the examples will have the designations given below.

I. 2,6-di-tert-butyl-a-dimethylamino-p-cresol II. 3,S-di-tert-butyl-4-hydroxy-N,N-dimethylthiobenzarnide III. 2,6-di-tert-butyl-4-(l-dimethylamino-Z-methyl-npropyl phenol IV. 6-tert-butyl-e' -dimethylamino-2,4-xylenol V. u,a-(1,4-piperazinediyl)bis(2,6-di-tert-butyl-pcresol) VI. 6-cyclohexyl-a -dimethylamino-2,4-xylenol VII. one-(2,6-diethylphenylimino)bis(2,6-di-tertbutyl-p-cresol) VIII. u,a'-(methylimino)bis(2,G-di-tert-butyl-p-cresol) IX. m-climethylamino-2,6bis(a,a-dimethylbenzyl)-p cresol X. a-dimethylamino-2,6-diisopropyl-p-cresol XI. e,a',a"-nitrilotris(2,G-di-tert-butyl-p-cresol) XII. 2,2-(3,5-di-tert-butyl-4-hydroxybenzylimino) diethanol I XIII. a,a'-(1,4-piperazinediyl)bis(3,5-di-tert-butyl-4- hydroxythiobenzaldehyde) XIV. 2,6-di-tert-butyl-4-[morpholino (thiocarbonyl)] phenol XV. a-dimethylamino-2,6-bis(e-methylbenzyl)-p-cresol EXAMPLE 1 Compound I is compressed into tablets of 10 mg. each which can be administered orally as antihypercholesterolemic agents.

EXAMPLE 2 Five hundred mg. of Compound II are mixed with mg. of lactose and filled into a No. 2 hard gelatin capsule.

EXAMPLE 3 Fifty gms. of Compound III, 10 gms. of calcium sulfate and 25 gms. of sucrose are thoroughly mixed and granulated with hot 10 percent gelatin solution. The wetted mass is passed through a No. 16 US. standard mesh screen directly onto drying trays. The granules are dried at F. and passed through a No. 20 US. standard mesh screen. These granules are then mixed with 15 gms. starch, 5 gms. talc and 3 gms. stearic acid, passed through a No. 60 US. standard mesh screen and then compressed into tablets containing mg. of active ingredient.

Seventy-five mg. of Compound IV are mixed with 225 mg. of peanut oil to a thick slurry and filled into a soft gelatin capsule.

EXAMPLE Linguets are obtained by combining the following com ponents:

Mg. Compound VI 25 Lactose 50 Confectioners sugar 60 Stearin 2 Talc l3 EXAMPLE 7 To a mixture of 140 gms. of Compound VII and 33.7 gms. of corn oil are added 3 gms. of gum acacia and 1.5 gms. of gum tragacanth. To the thoroughly triturated mixture is added slowly with stirring a solution of 0.1 gms. of a cetyl alcohol polyoxyethylene condensate, 40 gms. of cane sugar, 0.03 gms. of propyl-p-hydroxybenzoate, 0.3 gms. of methyl-p-hydroxybenzoate, 0.002 gm. of edible dyestufi and 110 gms. of water. After the incorporation of a suitable flavoring agent, such as imitation wild cherry, the mixture is homogenized by passage through a conventional homogenizer and there is thus obtained an emulsion suitable for oral administration in accordance with the present invention. The emulsion is bottled in half-pint bottles.

EXAMPLE 8 Ten gms. of Compound IX are dissolved in a mixture of 83 gms. of water, 250 gms. glycerol and 125 gms. of ethyl alcohol. To the resultant solution is added a solution of 300 gms. of sucrose and 150 gms. of water. By the incorporation of a suitable flavoring agent and coloring material there is obtained a syrup suitable for oral administration in accordance with the present invention.

EXAMPLE 10 Twenty-five gms. of sodium glycerophosphate, 25 gms. of calcium glycerophosphate and 50 gms. of Compound X are intimately mixed. The mixture is added gradually to 900 gms. of soluble casein in a'conventional mixer and mixed until homogenous. There is thus obtained a dietary supplement suitable for oral administration in accordance with this invention.

EXAMPLE 11 An intimate mixture is prepared with conventional mixing equipment of 3 gms. of pyridoxine hydrochloride, 100 gms. of nicotinic acid, 100 gms. of nicotinamide, 5 gms. of methionine, 15 gms. of choline bitararate, 150 gms. of ascorbic acid, 5 gms. of calcium pantothenate, 10 gms. of riboflavin and 1000 gms. of Compound XI. The mixture is filled into capsules which are then suitable for oral ad ministration in accordance with this invention.

10 EXAMPLE 12 Three hundred and eighty-two gms. of propylene glycol are agitated for one hour while saturating with nitrogen gas. Twelve and four-tenths gms. of Compound XII are then added and the mixture is stirred for 30 minutes more. Then cc. of nitrogen saturated water is slowly added. After 5 minutes of further stirring 7.85 cc. of monoethanolamine is added. Throughout the addition of ingredients the temperature is maintained below 30 C. by cooling as required. Solution is completed by stirring under nitrogen. The resulting 500 cc. of clear, light-colored solution contains approximately 50 mg./ cc. of Compound XII and is slightly alkaline. It is subdivided and samples are filled under nitrogen into 10 cc. multidose vials sealed with butyl rubber stoppers. Three cc. doses can be withdrawn in the standrad manner, by piercing the stopper witha hypodermic needle, injecting air and withdrawing the solution into the syringe. In this manner parenteral doses containing mg. of Compound XII are provided.

Following the procedure of Example 12, pharmaceutical solutions suitable for intravenous and intramuscular administration are prepared according to the following formulations and packaged under nitrogen.

EXAMPLE 13 Compound XIII gm 66.6 Monoethanolamine cc 22.1 Lidocaine gm 10 Propylene glycol gm 275 Water to make 400 cc.s.

The above solution contains 150 mgs./cc. of Compound XIII and can be administered intramuscularly in 1 cc. doses, once a day, giving a daily dosage of 150 mgs.

EXAMPLE l4 Glycerin, U.S.P. l 1 Compound XIV Glycerine, U.S.P., to make 2 liters The above solution contains 5 mgs./cc. of Compound XIV and can be administered intravenously in three 1 cc. dosage units to give a daily dosage of 15 mgs.

EXAMPL'E 15 Compound XV Glycerine, U.S.P. to make 1 liter.

XVI. a-Dimethylamino-p-cresol XVII. 6-tert-butyIPa -dimethyIamino-Z,4-xylenol EXAMPLE 16 Examples 1-4 are repeated using Compound XVI in place of Compounds I-IV to prepare tablets and capsules containing analogous amounts of Compound XVI.

EXAMPLE 17 Examples l-4 are repeated using Compound XVII in place of Compounds I-IV to prepare tablets and capsules containing analogous amounts of Compound XVH.

This invention has been extended to the use of a, a a -tris(dimethylamino) mesitol which can be made by the method within J. Am. Chem. Soc. 63, 270 (1941). Thus,

side chains about the phenolic nucleus can have the configuration (as also shown for example by 2,6.:di-tert-butyl-a-dimeth ylamino-p-cresol) and such side chains can take. the place of hydrocarbyl side .ehains bonded to the phenolio nuclei in Formulas I and II hereinabove. This suggeststhat the CH N(CH group and the related groups within wherein the various. Rs are independently selected. from hydrogen and lower alkyl. of fromone toeight carbons (or higher alkyls) can beutilized also in place of the various R's and other ring substituents in the three structural formulas on pp. 1 and 2 of'application Ser. No. 705,295, filed Feb. 14, 1968; Formulas I,'II, III and IV of application Ser. No. 647,582

filed May 8, 1967;

12 the structural formulas on pp. 1 and 2 of application Ser. No, 70f1,5 58 filed Feb. 12, 1968; now abandoned; the structural formulas on pp. 1, 2 and 3 of application Ser. No.704,228 filed on Feb. 9, 1968; and Formulas I, II, and III of application Ser. No. 347,357

filed Feb. 26, 1964, now abandoned.

References Cited I "Chem. (AbSt- Subject Index, vol. 66-75 (1967-1971), p. 50538.

SAMjROSEN, Primary Examiner 

